Relative importance of aldose reductase versus nonenzymatic glycosylation on sugar cataract formation in diabetic rats

The relative importance of sorbitol formation versus nonenzymatic glycosyla tion and advanced glycosylation end products (AGEs) on sugar cataract forma tion was examined in diabetic rats. Diabetes was experimentally induced in young, 50 g rats with streptozotocin, and aldose reductase inhibitors were administered in the diet for up to 8 weeks at concentrations of 0.06% for t olrestat or ponalrestat and 0.0125% for AL-1576. Cataract formation was mon itored by hand-held slit lamp for up to 11 weeks. Lens polyol levels were m onitored by GLC, glycosylated protein levels were spectrophotometrically de termined, and AGE products were estimated by fluorescence measurements and ELISA. Sugar cataract formation was observed in all untreated diabetic rats while cataract formation was inhibited in all diabetic rats treated with the AR i nhibitors. Lens sorbitol levels were reduced in all ARI-treated rats. Glyco sylated lens protein levels were elevated in the diabetic rats, and these l evels were not significantly lower in the non-cataractous lenses from ARI-t reated diabetic rats. Fluorescence measurements of the lens proteins reveal ed increased lens AGE levels in all diabetic rats, and these were slightly reduced in the aldose reductase inhibitor treated diabetics. With ELISA, im munoreactive AGEs were only detected in cataractous lenses from the untreat ed diabetic rats. Immunoreactive AGEs were not detected in the clear lenses of the aldose reductase inhibitor treated diabetics or in the non-diabetic controls. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalyzed intracellular accumulation o f polyols and that these sugar cataracts can be prevented through inhibitio n of aldose reductase.